The rapid increase in the incidence of gram-positive infections—including those caused by resistant bacteria—has sparked renewed interest in the development of novel classes of antibiotics. One such class is the lipopeptide antibiotics, which includes daptomycin. Daptomycin has potent bactericidal activity in vitro against clinically relevant gram-positive bacteria that cause serious and life-threatening diseases. These bacteria include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide intermediary susceptible Staphylococcus aureus (GISA), coagulase-negative staphylococci (CNS), and penicillin-resistant Streptococcus pneumoniae (PRSP), for which there are very few therapeutic alternatives (see Tally et al., 1999, Exp. Opin. Invest. Drugs 8 1223-1238, hereafter “Tally”). Daptomycin provides a rapid, concentration-dependent bactericidal effect and a relatively prolonged concentration-dependent post-antibiotic effect in vivo.
Daptomycin is described in Baltz in Biotechnology of Antibiotics, 2nd Ed., ed. by W. R. Strohl (New York: Marcel Dekker, Inc.), 1997, pp. 415-435, hereafter “Baltz.” Daptomycin is a cyclic lipopeptide antibiotic that can be derived from the fermentation of Streptomyces roseosporus. It is comprised of a decanoyl side chain linked to the N-terminal tryptophan of a cyclic 13-amino acid peptide (see FIG. 1a, Baltz et al., supra). The compound is currently being developed in both intravenous and oral formulations to treat serious infections caused by bacteria, including, but not limited to, methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE).
Daptomycin's mechanism of action is distinct from that of other classes of antibiotics, which include β-lactams, aminoglycosides, glycopeptides and macrolides. Without wishing to be bound by any theory, daptomycin is believed to kill gram-positive bacteria by disrupting multiple aspects of bacterial plasma membrane function while not penetrating into the cytoplasm. The antibacterial mechanisms of daptomycin may include inhibition of peptidoglycan synthesis, inhibition of lipoteichoic acid synthesis and dissipation of bacterial membrane potential (see, e.g., Baltz, supra).
The efficacy and safety of daptomycin has been examined in nonclinical studies and in Phase I and Phase II clinical trials. Daptomycin was well tolerated in human volunteers when given intravenously at 1 or 2 mg/kg every 24 hours. See Baltz, supra, and references therein. Furthermore, a single dose of daptomycin was well-tolerated over a dose range of 0.5 to 6 mg/kg. See Baltz, supra, and Woodworth et al., 1992, Antimicrob. Agents Chemother. 36:318-25. However, prolonged treatment with 3 mg/kg daptomycin every 12 hours was shown to cause occasional adverse effects (Baltz, supra). Transient muscular weakness and pain were observed in two of five human patients who had been treated with 4 mg/kg daptomycin every 12 hours for 6 to 11 days (Tally, supra). In the two subjects who experienced muscular weakness and pain, creatine phosphokinase (CPK) levels had increased one to two days prior to the muscular weakness. Treatment was discontinued three to four days after the initial elevation in CPK was observed. One to two days after discontinuation of daptomycin treatment, CPK levels peaked at levels in excess of 10,000 U/L in one subject and at 20,812 U/L in the second subject (Tally, supra). Based upon these studies and the rationale that higher doses of daptomycin were required for efficacy against many types of bacterial infection, clinical studies of daptomycin were discontinued (Baltz, supra).
In the above-described clinical trials and in a series of toxicology studies in animals, skeletal muscle was found to be the primary target tissue of daptomycin toxicity. Repeated daily intravenous administration in toxicological studies of high doses of daptomycin in rats and dogs (75 mg/kg/day in rats and 40 mg/kg/day in dogs) caused mild myopathy in the skeletal muscle (Tally, supra). It was also found that increases in CPK levels are a sensitive measure of myopathy, and thus can be used to measure daptomycin's effects upon muscle tissue. See Tally et al. supra.
Although low doses of daptomycin do not cause muscle toxicity and are effective in treating many gram-positive bacterial infections, certain types of gram-positive bacterial infections, such as deep-seated infections or those caused by certain antibiotic-resistant bacterial strains, may require higher doses of daptomycin for effective treatment. For instance, certain vancomycin-resistant strains of bacteria exhibit a two- to four-fold higher daptomycin minimum inhibitory concentration (MIC) than most vancomycin-susceptible strains. Accordingly, there is a great need to develop methods for administration of effective amounts of daptomycin that will also minimize adverse skeletal muscle effects.
A non-lipopeptide streptogramin antibiotic combination, quinupristin/dalfopristin, has also shown activity against gram-positive organisms, including antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus, glycopeptide intermediary S. aureus, and glycopeptide-resistant Enterococcus faecium (Rubinstein et al., 1999, J. Antimicrob. Chemother. 44, Topic A, 37-46, hereafter “Rubinstein”). Quinupristin/dalfopristin has been shown to be effective in treatment of nosocomial pneumonia, emergency use studies, complicated skin and skin structure infection and bacteremia (Rubinstein, supra). Approximately 13% of the patients treated with 7.5 mg/kg quinupristin/dalfopristin every 8 or 12 hours experienced arthralgia or myalgia, which included muscle pain, and approximately 5% of patients exhibited increased CPK levels (Rubinstein, supra). Therefore, it would appear that quinupristin/dalfopristin also causes muscle toxicity.
The aminoglycosides, which make up another class of antibiotics, are also toxic at high doses. They have been administered as a high dose at less frequent intervals rather than at lower doses at more frequent intervals in order to reduce their toxicity (Barclay et al., 1994, Clin. Pharmacokinet. 27:32-48). However, aminoglycosides differ from daptomycin in a number of ways, specifically in the fact that the sites of toxicity are distinct. Aminoglycosides are toxic to the kidney and central nervous system whereas skeletal muscle is the site of toxicity for daptomycin. The mechanisms of toxicity for aminoglycosides and daptomycin are also distinct. In addition, aminoglycosides are structurally dissimilar to daptomycin, act only on gram-negative bacteria, have a different mechanism of antibacterial action from daptomycin and exhibit different mechanisms of resistance. Thus, the possibility that less frequent administration of aminoglycosides results in lower toxicity to the patient does not predict that the same would be true for daptomycin.